USPTO Patents Application 09584978

Washington DC 20231
USA

From: AGYS PHARMA
Dr. Rudi Neirinckx
3, Rue du Vignobie
F- 68 440 DIETWILLER
FRANCE

Concerning : Patent Application

Dear Conmiissioner,

Please find enclosed an application for a U.S. Patent, entitled "Treatment of psoriasis through
down-regulation of the EGF-receptor with topically-applied EGF".
Please send all correspondence to me at the above-mentioned address,

I thank you in advance,

Yours sincerely.

Dr. Rudi Neirinckx

Kruger Phurma s.a.r.L

ceo

AGYS PHARMA® nv Industrieweg 1 1 8, Bus 1 B-9032 Wondelgem/Gent - Belgium

Tel. 00-32-9-216 27 10
Fax 00-32-9-216 27 13 Fax 00-32-9-216 68 80
E-mail: ^ivsphaniia@,pi.be
BTW BE 467.140.419 HRG 194 357

TREATMENT OF PSORIASIS THROUGH DOWN-REGULATION OF THE
EGF-RECEPTOR WITH TOPICALLY- APPLIED EGF .

R.D* Neirinckx
ABSTRACT

From unrelated but similar fields it is deduced that certain forms of psoriasis can
be effectively treated through topical application of EGF-containing
formulations. This patent application summarizes the theoretical basis for this
finding and requests protection for the idea, while clinical evaluation is in
preparation.

INTRODUCTION

Psoriasis is a chronic sidn disorder that affects approximately 4.0 million
people in the US., and annual treatment costs in the USA alone are
estimated at over $1.5 billion. There are no currently available drugs for
this disease that offer satisfactory efficacy and safety. Psoriatic lesions are
caused by the hyperproliferation of keratinocytes, but it has been
demonstrated that EGF-R signalling is required for the growth of
keratinocytes.

It has been demonstrated that the upper epidermal layer in psoriatic tissue
contains levels of EGF-receptors (EGFR) more similar to the levels found in the
mitotically-active basal cell layer of skin. In normal epidermis r-EGF is located
primarily in the germinative layer , which contains r-EGF levels 4 times higher
than those found in the more-diferentiated ceUs of the upper epidermal layers. In
psoriatic lesions the upper epidermal layers shows r-EGF levels 2x higher than in
normal tissue, while the germanitive layer has normal levels.( L. A. Nanney et al;
J. Invest.Dermat. Vol 85, p 260-265 ).

There is only a poor correlation between the levels of r-EGF and the level of
cellular proliferation. An example of cells with elevated metabolism but low
mitotic activity is the case of the sweat duct epithelium. Similarly, the high level
of r-EGF indicates elevated metabolism rather than lack of differentiation in
psoriatic lesions.

PROPOSAL

As the main difference in r-EGF distribution in normal and psoriatic tissue is the
abnormal retention of the receptor beyond the first 2-3 ceU rows in the stratum
basilis in psoriatic tissue , we propose to reduce these concentrations through a
down regulation of the receptor using higher than normal levels of EGF at the
level of the receptor.

This is similar to the down regulation of FSH and LH excretion through the
saturation of pituitary GnRH receptors in response to a constant level of GnRH .

This down regulation is due to the deviation from the normal physiological
situation where intermittent surges of GnRH release LH and FSH ^without
causing saturation of the receptors. It is also similar to the effect of high levels of
estradiol on estrogen-dependent tumour lines: In-vitro , the proliferation of these
cells can be halted by high, non-physiological concentrations of the hormone.

It has been reported that high levels of EGF have inhibited the growth of EGF-
dependent cancer cell lines in-vitro. The biological activity of epidermal growth
factor (EGF) is mediated through the intrinsic tyrosine kinase activity of the EGF
receptor (EGFR). In numerous cell types, binding of EGF to the EGFR
stimulates the tyrosine kinase activity of the receptor eventually leading to cell
proliferation. In tumor-derived cell lines, which overexpress the EGFR, however,
growth inhibition is often seen in response to EGF. The mechanism for growth
inhibition is unclear. A constant pressure of EGF may engender a similar down
regulation of the EGF receptors and result in a more-normal metabolic activity
and a reversion of psoriatic tissue to normal.

CLINICAL EVALUATION

Two patients, suffering from psoriasis , were treated with a topical cream
containing sulfadiazine and 5 ^ig of EGF/ gram of cream. The treatment was
carried out by applying 2 grams of cream over each psoriatic lesion and was
carried out twice a day for a week.

RESULTS AND CONCLUSION

After a week's treatment the psoriatic lesions showed - subjectively - a marked
improvement , comparable to the result obtained after treatment with
corticosteroids.

It is therefore felt that a larger clinical trial is warranted.

CLAIMS

1. Topical treatment of psoriasis with formulations (creams, gels,...) to
accomplish non-physiologic high concentrations of Epidermal Growth
Factor (EGF), which can down-regulate the expression of the EGF-
Receptor .

2. Psoriasis treatment with topical formulations ,containing EGF in
concentrations of 0.01 to to 50 micrograms/ gram.

3. Topical formulations containing 0.5-20 microgram EGF / gram of
formulation .

4. Topical creams , containing 0.1-3% sulfadiazine and 0.5-20 micrograms
EGF / gram for the treatment of psoriasis.

5. Topical formulations, containing anti-inflammatory products , in
combination with epidermal growth factor.

6. Topical formulations, containing EGF in combination with anti-
inflammatory products and other dermatologkally-beneficial products ,
for the treatment of proriasis.

7. Topical formulations , containing 10 ^g EGF and 1% of sulfadiazine for
the treatment of psoriasis.

8. Systemic treatment of psoriasis patients with 0.001 - 10 microgram of
EGF /kg.

9. Topical and systemic treatment of psoriasis patients with precursor
molecules of epidermal growth factor ,such as^flbroblast growth factor.

10. Treatment with products, with similar biolc^cal action as EGF, such as
urogastrone or fractions of the EGF molecule.